A series of clinical studies, now broadly confirmed, has shown that L-triiodothyronine will accelerate the antidepressant effect of imipramine in women, though not in men. Thyroid stimulating hormone (TSH) shares this property but ethinyl estradiol has variable effects. Preliminary evidence suggests that methyl testosterone given with imipramine, converts depressive illness in men to paranoid disorder. Systematic trials will be conducted to determine whether smaller doses of testosterone will accelerate the antidepressant action of imipramine in men without precipitating a delusional syndrome. Studies of thyroid state in depression and of thyroid hormones as adjuncts in the remendy of depression led to studies of thyrotropin releasing hormone (TRH), a hypothalamic substance that, with other factors, modulates the secretion of TSH and thyroid hormones. Controlled studies suggest that TRH by itself has immediate, though brief, antidepressant action. We plan to study the mechanism of this action and to determine whether repeated doses of TRH are safe and exert a definitive antidepressant effect. In addition we will pursue the tentative findings that TRH may have value in certain cases of schizophrenia and in the hyperkinetic syndrome of children. In animals, behavioral and biochemical studies will be directed at elucidating the central actions of TRH and of other hypothalamic releasing hormones as they become available. The remarkable ability of TRH to antagonize pentobarbital will be studied in detail. Pentobarbital antagonism will be used as a screening test for possible central action of synthetic congeners of TRH. The premise that TRH and presumably other brain releasing hormones have central actions as well as pituitary actions seems increasingly well-founded. It opens a new area of neurobiology and a new approach to the remedy of mental illness.